Downregulation of the tyrosine degradation pathway extends Drosophila lifespan

Aging is characterized by extensive metabolic reprogramming. To identify metabolic pathways associated with aging, we analyzed age-dependent changes in the metabolomes of long-lived . Among the metabolites that changed, levels of tyrosine were increased with age in long-lived flies. We demonstrate t...

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Veröffentlicht in:eLife 2020-12, Vol.9
Hauptverfasser: Parkhitko, Andrey A, Ramesh, Divya, Wang, Lin, Leshchiner, Dmitry, Filine, Elizabeth, Binari, Richard, Olsen, Abby L, Asara, John M, Cracan, Valentin, Rabinowitz, Joshua D, Brockmann, Axel, Perrimon, Norbert
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Sprache:eng
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Zusammenfassung:Aging is characterized by extensive metabolic reprogramming. To identify metabolic pathways associated with aging, we analyzed age-dependent changes in the metabolomes of long-lived . Among the metabolites that changed, levels of tyrosine were increased with age in long-lived flies. We demonstrate that the levels of enzymes in the tyrosine degradation pathway increase with age in wild-type flies. Whole-body and neuronal-specific downregulation of enzymes in the tyrosine degradation pathway significantly extends lifespan, causes alterations of metabolites associated with increased lifespan, and upregulates the levels of tyrosine-derived neuromediators. Moreover, feeding wild-type flies with tyrosine increased their lifespan. Mechanistically, we show that suppression of ETC complex I drives the upregulation of enzymes in the tyrosine degradation pathway, an effect that can be rescued by tigecycline, an FDA-approved drug that specifically suppresses mitochondrial translation. In addition, tyrosine supplementation partially rescued lifespan of flies with ETC complex I suppression. Altogether, our study highlights the tyrosine degradation pathway as a regulator of longevity.
ISSN:2050-084X
2050-084X
DOI:10.7554/eLife.58053